BACKGROUND: The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGFβ) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGFβ signaling in prostate cancer-induced bone metastasis using a novel human prostate cancer cell line, PacMetUT1. METHODS: We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGFβ signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay. RESULTS: Osteoblastic bone metastasis in skull, rib, and femur was detected after 10-16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGFβ1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan TGFβ binding protein (BG(E) RII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment. CONCLUSIONS: Our results for the first time indicate that blockade of TGFβ signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGFβ signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis.
BACKGROUND: The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGFβ) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGFβ signaling in prostate cancer-induced bone metastasis using a novel humanprostate cancer cell line, PacMetUT1. METHODS: We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGFβ signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay. RESULTS:Osteoblastic bone metastasis in skull, rib, and femur was detected after 10-16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGFβ1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan TGFβ binding protein (BG(E) RII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment. CONCLUSIONS: Our results for the first time indicate that blockade of TGFβ signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGFβ signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis.
Authors: Juswinder Singh; Claudio E Chuaqui; P Ann Boriack-Sjodin; Wen Cherng Lee; Timothy Pontz; Michael J Corbley; H-Kam Cheung; Robert M Arduini; Jonathan N Mead; Miki N Newman; James L Papadatos; Scott Bowes; Serene Josiah; Leona E Ling Journal: Bioorg Med Chem Lett Date: 2003-12-15 Impact factor: 2.823
Authors: H Nawata; S Tanaka; S Tanaka; R Takayanagi; Y Sakai; T Yanase; S Ikuyama; M Haji Journal: J Steroid Biochem Mol Biol Date: 1995-06 Impact factor: 4.292
Authors: Bethany A Kerr; Koran S Harris; Lihong Shi; Jeffrey S Willey; David R Soto-Pantoja; Tatiana V Byzova Journal: Am J Clin Exp Urol Date: 2021-02-15
Authors: Xinhai Wan; Zhi-Gang Li; Jonathan M Yingling; Jun Yang; Michael W Starbuck; Murali K Ravoori; Vikas Kundra; Elba Vazquez; Nora M Navone Journal: Bone Date: 2011-12-07 Impact factor: 4.398
Authors: Xiaoxin Mu; Shu Lin; Junhua Yang; Chen Chen; Yun Chen; Maryanne C Herzig; Kenneth Washburn; Glenn A Halff; Christi A Walter; Beicheng Sun; Lu-Zhe Sun Journal: PLoS One Date: 2013-05-21 Impact factor: 3.240